Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase (known as "matrix metalloproteinases", and herein referred to as MMPs) are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth.
Tumour necrosis factor (herein referred to as "TNF") is a cytokine which is produced initially as a cell-associated 28kD precursor. It is released as an active. 17kD form . which can mediate a large number of deleterious effects in vivo. When administered to animals or humans it causes inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration can also cause cachexia and anorexia. Accumulation of excessive TNF can be lethal.
There is considerable evidence from animal model studies that blocking the effects of TNF with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal haematopoiesis in patients with these tumours.
Compounds which inhibit the production or action of TNF are therefore thought to be potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Since excessive TNF production has been noted in several diseases or conditions also characterised by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may have particular advantages in the treatment or prophylaxis of diseases or conditions in which both mechanisms are involved.
Several classes of MMP inhibitors have been proposed, including derivatives of hydroxamic acid. The following patent publications disclose hydroxamic acid-based MMP inhibitors:
US 4599361 (Searle) PA1 EP-A-0236872 (Roche) PA1 EP-A-0274453 (Bellon) PA1 WO 90/05716 (British Bio-technology) PA1 WO 90/05719 (British Bio-technology) PA1 WO 91/02716 (British Bio-technology) PA1 EP-A-0489577 (Celltech) PA1 EP-A-0489579 (Celltech) PA1 EP-A-0497192 (Roche) PA1 WO 92/13831 (British Bio-technology) PA1 WO 92/22523 (Research Corporation Technologies) PA1 WO 93/09090 (Yamanouchi) PA1 WO 93/09097 (Sankyo) PA1 WO 93/20047 (British Bio-technology) PA1 WO 93/24449 (Celltech) PA1 WO 93/24475 (Celltech) PA1 EP-A-0574758 (Roche)
The intrinsic potency of compounds within the broad structural groups of hydroxamic derivatives disclosed in the above publications against particular MMPs can be high. For example, many have a collagenase IC.sub.50 by the in vitro test method of Cawston and Barrett, (Anal. Biochem., 99, 340-345, 1979) of less than 50 nM. Unfortunately, however, the physicochemical and/or pharmacokinetic properties of the specific compounds disclosed in those publications have generally been disappointing. Identifying hydroxamic acid-based MMP inhibitors having a good balance of high intrinsic activity against the target MMPs, and good physicochemical and/or pharmacokinetic properties, such that the compounds are easily formulated for administration, have good bioavailability for acceptable periods following administration, and have high in vivo activity in the target disease or condition, remains a much sought after goal in the art.
The hydroxamic acid derivatives disclosed in the above publications can be regarded as having the following basic structure (IA): ##STR1## wherein the five substituents R.sub.1 -R.sub.5 may vary according to the detailed disclosure of each publication. The balance of intrinsic level of activity, degree of specificity of inhibition of particular categories of MMP, physicochemical and pharmacokinetic properties can vary in an unpredictable way as the substituents R.sub.1 -R.sub.5 are varied.
Of the above publications, only EP-A-0236872 refers to the possibility that in a particular class of collagenase inhibitors of basic structure (lA) the substituent R.sub.1, may be OH. That possibility is referred to amongst many other possible R.sub.1. substituents, in the context of compounds in which the substituent R.sub.3 is the characteristic side chain of a naturally occurring amino acid in which any functional substituents may be protected, any amino group may be acylated, and any carboxyl group may be esterified. EP-A-0236872 does not disclose such compounds as having preferred or particularly advantageous collagenase inhibitory properties, and in fact contains no disclosure of any specific compound in which R.sub.1. is hydroxy. It does not address the problem in the art referred to above of providing hydroxamic acid derived MMP inhibitors having the elusive balance of good intrinsic activity profile and good physicochemical and pharmacokinetic properties.